Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622001193763p
Ethics application status
Submitted, not yet approved
Date submitted
3/08/2022
Date registered
6/09/2022
Date last updated
6/09/2022
Date data sharing statement initially provided
6/09/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
Phosphate Replacement In Critical Illness: the PRICE-1 trial
Scientific title
The effect of liberal versus restrictive phosphate replacement on total phosphate administration in adult critically ill patients: a Phase-2 cluster, crossover, database-integrated, randomised, controlled trial
Secondary ID [1] 307367 0
Nil Known
Universal Trial Number (UTN)
U1111-1279-4796
Trial acronym
PRICE-1
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Derangement of serum phosphate concentrations 326714 0
Condition category
Condition code
Metabolic and Endocrine 323955 323955 0 0
Other metabolic disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Three ICUs will be randomised to use either the restrictive or liberal phosphate replacement protocol for a three-month period, followed by a one-month washout period. The sites will then crossover to the alternate phosphate replacement protocol for another three-month period.

For the duration of the trial, all patients admitted to participating ICUs will have phosphate replacement delivered as per the study-allocated phosphate replacement protocol. Clinicians may determine whether oral or intravenous replacement should be administered, as well as the dose and frequency of replacement. The PRICE-1 trial will only stipulate the threshold at which phosphate replacement may be initiated.

The restrictive protocol will stipulate phosphate replacement to commence at a threshold of 0.50 mmol/L, and the liberal protocol at 0.80 mmol/L. All other treatment will be at the discretion of the treating clinician.

During the first study period, the three participating ICUs will be randomised to either the restrictive or liberal phosphate replacement protocol. At the completion of the first study period (i.e., after three months), there will be a one-month washout period. For the second study period, the ICUs will crossover to the alternate phosphate replacement protocol i.e., if ICU-A used the restrictive protocol for the first study period, it will crossover to the liberal protocol for the second study period, and vice versa.

The use of the allocated protocol and adherence to the protocol will be monitored using electronic medical records.
Intervention code [1] 323837 0
Treatment: Other
Comparator / control treatment
The restrictive protocol will stipulate phosphate replacement to commence at a threshold of 0.50 mmol/L, and the liberal protocol at 0.80 mmol/L.

The liberal phosphate replacement protocol, which is modeled current practices in the participating ICUs, will serve as the comparator.
Control group
Active

Outcomes
Primary outcome [1] 331763 0
Difference in total phosphate replacement (measured in mmol and including both oral and intravenous replacement) between the restrictive and liberal phosphate replacement groups.

This is a composite outcome comprising oral and intravenous phosphate. This data will be collected by extraction from the electronic medical record using pre-tested Structure Query Language (SQL) scripts.
Timepoint [1] 331763 0
Duration of ICU admission as recorded in the electronic medical record
Secondary outcome [1] 411053 0
Quantities of intravenous phosphate replaced
Timepoint [1] 411053 0
Duration of ICU admission as recorded in the electronic medical record
Secondary outcome [2] 411055 0
ICU length of stay
Timepoint [2] 411055 0
Duration of ICU admission as recorded in the electronic medical record
Secondary outcome [3] 411056 0
ICU mortality
Timepoint [3] 411056 0
Duration of ICU admission as recorded in the electronic medical record
Secondary outcome [4] 411057 0
Acute kidney injury (defined as increase in serum creatinine to greater than or equal to 1.5 times baseline serum creatinine determined by hospital medical record review)
Timepoint [4] 411057 0
Duration of ICU admission as recorded in the electronic medical record
Secondary outcome [5] 411058 0
Symptomatic cardiac rhythm disturbance determined by electronic medical record review
Timepoint [5] 411058 0
Duration of ICU admission as recorded in the electronic medical record
Secondary outcome [6] 411059 0
Mechanical ventilation hours determined by electronic medical record review
Timepoint [6] 411059 0
Duration of ICU admission as recorded in the electronic medical record
Secondary outcome [7] 411060 0
Tracheal reintubation determined by electronic medical record review
Timepoint [7] 411060 0
Duration of ICU admission as recorded in the electronic medical record
Secondary outcome [8] 411061 0
Tracheostomy insertion determined by electronic medical record review
Timepoint [8] 411061 0
Duration of ICU admission as recorded in the electronic medical record
Secondary outcome [9] 412574 0
Quantity of intravenous phosphate replaced determined by electronic medical record review
Timepoint [9] 412574 0
Duration of ICU admission as recorded in the electronic medical record
Secondary outcome [10] 412575 0
Hospital mortality
Timepoint [10] 412575 0
Duration of hospital admission as recorded in the hospital medical record
Secondary outcome [11] 412581 0
Proportion of patients receiving phosphate replacement determined by electronic medical record review
Timepoint [11] 412581 0
Duration of ICU admission as recorded in the electronic medical record
Secondary outcome [12] 412582 0
Acceptability of phosphate replacement protocols among doctors and nurses working in participating ICUs determined by surveys conducted during the last week of each of the two study periods. A custom-designed survey, pilot-tested within the investigators' group, was developed for this purpose.
Timepoint [12] 412582 0
Last week of recruitment into each of the two study periods
Secondary outcome [13] 412584 0
Effective database-integration (defined as ability to extract 100% of patient data required for the trial through automated data extraction without the need for manual data collection). To calculate this percentage, a denominator and numerator are required. The total number of data points required, which form the denominator, are pre-specified. The numerator consists of data points which are able to be extracted by the automated data extraction process.
Timepoint [13] 412584 0
At completion of trial
Secondary outcome [14] 412585 0
Feasibility. This is a composite outcome incorporating both acceptability of the phosphate replacement protocols ((assessed using study-specific surveys during the last week of recruitment in each of the two study periods) and effectiveness of database-integration (by calculating the percentage of data which is extracted using the automated data extraction process) (as defined in secondary outcomes 12 and 13)
Timepoint [14] 412585 0
At completion of trial

Eligibility
Key inclusion criteria
All patients admitted to the participating ICUs during the study period
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1) Patients admitted solely for provision of palliative care or awaiting organ donation
2) Patients who have already been included in the PRICE-1 trial (i.e., only the first ICU admission for each patient during the trial will be eligible for inclusion in the trial)

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation will not be concealed.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation will be performed using computer-generated tables to allocate sites to the restrictive or liberal phosphate replacement protocol.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
Cluster crossover trial
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Continuous data will be assessed for normality and presented as either mean or standard deviation (SD) or median and interquartile range (IQR). Categorical data will be presented as numbers and proportions. The primary outcome, difference in phosphate replacement between the two groups will be compared using (depending on normality) either an equality of medians or student t-test with appropriate adjustment for clustering. Among the other feasibility outcomes, protocol compliance will be assessed based on separation of daily serum phosphate concentrations. Acceptability of the two phosphate replacement protocols will be assessed using a short survey of ICU clinicians (doctors, nurses and pharmacists) at participating sites. The proportion of ICU patients receiving any phosphate replacement during their ICU admission will be compared using a Pearson chi-squared test. The database integration outcome will be assessed descriptively. Formal significance testing will only be performed for the primary outcome and for the difference in proportion of patients receiving any phosphate replacement. A p-value of <0.05 will be considered significant. The clinical outcomes will be assessed using appropriate methods adjusting for clustering and will be presented as odds ratio or mean difference with 95% confidence intervals without p-vales.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/11/2022
Actual
Date of last participant enrolment
Anticipated
1/09/2023
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
1700
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 22606 0
Caboolture Hospital - Caboolture
Recruitment hospital [2] 22607 0
Redcliffe Hospital - Redcliffe
Recruitment hospital [3] 22608 0
Royal Brisbane & Womens Hospital - Herston
Recruitment postcode(s) [1] 37867 0
4020 - Redcliffe
Recruitment postcode(s) [2] 37868 0
4029 - Herston
Recruitment postcode(s) [3] 37866 0
4510 - Caboolture

Funding & Sponsors
Funding source category [1] 311650 0
Other
Name [1] 311650 0
Metro North Hospital and Health Services
Country [1] 311650 0
Australia
Primary sponsor type
Other Collaborative groups
Name
The PRICE-1 Trial Investigators
Address
Metro North Hospital and Health Services
Royal Brisbane and Women's Hospital
Butterfield St
Herston QLD 4029
Country
Australia
Secondary sponsor category [1] 313423 0
None
Name [1] 313423 0
Address [1] 313423 0
Country [1] 313423 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 311105 0
Metro South Human Research Ethics Committee
Ethics committee address [1] 311105 0
Human Research Ethics Office
Princess Alexandra Hospital
199 Ipswich Road
WOOLLOONGABBA, QLD, 4102
Ethics committee country [1] 311105 0
Australia
Date submitted for ethics approval [1] 311105 0
03/08/2022
Approval date [1] 311105 0
Ethics approval number [1] 311105 0

Summary
Brief summary
Derangements of serum phosphate concentrations, specifically hypophosphataemia, are common among ICU patients and our previous work has suggested this may be associated with worse clinical outcomes, including higher mortality and morbidity. Although replacement of phosphate through both intravenous and enteral routes is common in ICUs, the optimum threshold of serum phosphate at which to commence active replacement in critically ill patients is currently unknown, and the benefits have never been confirmed with an RCT. Resultantly, there are no consensus guidelines on phosphate replacement in ICU, with individual ICUs and clinicians self determining thresholds at which to replace phosphate. Such treatment comes at significant cost and there are potential adverse outcomes associated with phosphate replacement including hypocalcaemia (potentially precipitous and life-threatening), nausea, vomiting, diarrhoea and hypotension. Thus, ICU clinicians are left with substantial uncertainty about the optimal threshold at which to replace phosphate.

Therefore, a clinical and ethical imperative exists to conduct a high-quality, investigator initiated, RCT to inform clinical practice with regards to phosphate replacement and its impacts on patient centred outcomes in critically ill patients.

The PRICE-1 RCT will compare the use of a restrictive phosphate replacement protocol against a liberal phosphate replacement protocol for the management of serum phosphate levels in critically ill patients. The liberal protocol will start replacing phosphate when the serum concentration is below 0.80 mmol/L, whereas the restrictive protocol will start replacement when the serum phosphate concentration is below 0.50 mmol/L. The choice of oral versus intravenous phosphate administration is determined by the functioning of the patient's gastrointestinal tract. All other aspects of patient care will be determined by the treating clinicians as is appropriate for the condition/s with which the patients are admitted to the Intensive Care Unit.

We hypothesise that use of a restrictive phosphate replacement protocol, compared to a liberal protocol, will result in reduced amount of phosphate replacement administered to critically ill patients in the Intensive Care Unit. Additionally, we hypothesise that the conduct of an electronic database-integrated cluster randomised trial will be feasible.
Trial website
Trial related presentations / publications
Public notes
Nil

Contacts
Principal investigator
Name 119962 0
Dr Mahesh Ramanan
Address 119962 0
ICU
Caboolture Hospital
McKean St, Caboolture QLD 4510
Country 119962 0
Australia
Phone 119962 0
+61 07 5316 5956
Fax 119962 0
Email 119962 0
mahesh.ramanan@health.qld.gov.au
Contact person for public queries
Name 119963 0
Dr Mahesh Ramanan
Address 119963 0
ICU
Caboolture Hospital
McKean St, Caboolture QLD 4510
Country 119963 0
Australia
Phone 119963 0
+61 07 5316 5956
Fax 119963 0
Email 119963 0
mahesh.ramanan@health.qld.gov.au
Contact person for scientific queries
Name 119964 0
Dr Mahesh Ramanan
Address 119964 0
ICU
Caboolture Hospital
McKean St, Caboolture QLD 4510
Country 119964 0
Australia
Phone 119964 0
+61 07 5316 5956
Fax 119964 0
Email 119964 0
mahesh.ramanan@health.qld.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
IPD sharing was not part of the ethics approval


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.